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Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing identified biallelic pathogenic mutations in known ACHM genes, including four novel variants. At baseline, the patients presented a reduced best corrected visual acuity (BCVA), reduced macular sensitivity (MS), normal dark-adapted electroretinogram (ERG) responses and undetectable or severely reduced light-adapted ERG. The longitudinal analysis of 16 patients (mean follow-up: 5.4 ± 1.0 years) showed a significant decline of BCVA (0.012 logMAR/year) and MS (-0.16 dB/year). Light-adapted and flicker ERG responses decreased below noise level in three and two patients, respectively. Only two patients (12.5%) progressed to a worst OCT grading during the follow-up. Our findings corroborate the notion that ACHM is a progressive disease in terms of BCVA, MS and ERG responses, and affects slowly the structural integrity of the retina. These observations can serve towards the development of guidelines for patient selection and intervention timing in forthcoming gene replacement therapies.
Assuntos
Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/patologia , Mutação , Adolescente , Adulto , Biomarcadores , Pré-Escolar , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Análise Mutacional de DNA , Proteínas do Olho/genética , Feminino , Proteínas Heterotriméricas de Ligação ao GTP/genética , Humanos , Estudos Longitudinais , Masculino , Linhagem , Fenótipo , Prognóstico , Estudos Retrospectivos , Tomografia de Coerência Óptica , Adulto JovemRESUMO
PURPOSE: To investigate the natural history of Stargardt disease over a multiyear follow-up. METHODS: We reviewed medical records of Stargardt disease patients, with clinical diagnosis of Stargardt disease at a single institution, which was also supported by molecular diagnosis. All patients underwent best-corrected visual acuity, fundus photography, optical coherence tomography, and full-field electroretinography. RESULTS: The study cohort consisted of 157 Stargardt disease patients aged 30.4 ± 1.1 years. Longitudinal analysis (mean follow-up: 3 years) showed a significant worsening of best-corrected visual acuity at an average rate of 1.5 Early Treatment Diabetic Retinopathy Study letters/year (P < 0.001), an enlargement of retinal pigment epithelium lesion area by optical coherence tomography at an average linear rate of 0.10 mm/year (P < 0.001), and a thinning of central macular thickness at a mean rate of -1.42 µm/year (P < 0.001). Survival analysis showed that patients with 2 alleles harboring likely-null variants, on average, reached most severe disease stage, i.e., legal blindness, alteration in both dark-adapted and light-adapted electroretinographic responses, and retinal pigment epithelium lesion area larger than 2.5 mm significantly earlier than patients with at least one allele harboring a missense variant. CONCLUSION: The current longitudinal study showed a significant genotype-phenotype correlation characterization, because patients harboring 2 likely-null alleles reach a severe disease stage about 10 years earlier than patients with at least one missense allele.
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Angiofluoresceinografia/métodos , Previsões , Oftalmoscopia/métodos , Epitélio Pigmentado da Retina/patologia , Doença de Stargardt/diagnóstico , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Progressão da Doença , Eletrorretinografia , Feminino , Seguimentos , Fundo de Olho , Estudos de Associação Genética , Humanos , Incidência , Itália/epidemiologia , Masculino , Mutação , Estudos Retrospectivos , Doença de Stargardt/epidemiologia , Doença de Stargardt/genéticaRESUMO
Retinitis pigmentosa (RP) is a clinically heterogenous disease that comprises a wide range of phenotypic and genetic subtypes. Pericentral RP is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved in pericentral RP. The aim of this study was to perform the first detailed clinical and genetic analysis of a cohort of European subjects with pericentral RP to determine the phenotypic features and the genetic bases of the disease. A total of 54 subjects from 48 independent families with pericentral RP, non-syndromic and syndromic, were evaluated through a full ophthalmological examination and underwent clinical exome or retinopathy gene panel sequencing. Disease-causative variants were identified in 22 of the 35 families (63%) in 10 different genes, four of which are also responsible for syndromic RP. Thirteen of the 34 likely pathogenic variants were novel. Intra-familiar variability was also observed. The current study confirms the mild phenotype of pericentral RP and extends the spectrum of genes associated with this condition.
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Retinose Pigmentar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Exoma , Feminino , Testes Genéticos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Linhagem , Retinose Pigmentar/epidemiologia , Adulto JovemRESUMO
PURPOSE: To evaluate differences in the visual phenotype and natural history of Usher syndrome caused by mutations in MYO7A or USH2A, the most commonly affected genes of Usher syndrome Type I (USH1) and Type II (USH2), respectively. METHODS: Eighty-eight patients with a clinical diagnosis of USH1 (26 patients) or USH2 (62 patients) were retrospectively evaluated. Of these, 48 patients had 2 disease-causing mutations in MYO7A (10 USH1 patients), USH2A (33 USH2 patients), and other USH (5 patients) genes. Clinical investigation included best-corrected visual acuity, Goldmann visual field, fundus photography, electroretinography, and audiologic and vestibular assessments. Longitudinal analysis was performed over a median follow-up time of 3.5 years. RESULTS: Patients carrying mutations in MYO7A had a younger age of onset of hearing and visual impairments than those carrying mutations in USH2A, leading to an earlier diagnosis of the disease in the former patients. Longitudinal analysis showed that visual acuity and visual field decreased more rapidly in subjects carrying MYO7A mutations than in those carrying USH2A mutations (mean annual exponential rates of decline of 3.92 vs. 3.44% and of 8.52 vs. 4.97%, respectively), and the former patients reached legal blindness on average 15 years earlier than the latter. CONCLUSION: The current study confirmed a more severe progression of the retinal disease in USH1 patients rather than in USH2 patients. Furthermore, most visual symptoms (i.e., night blindness, visual acuity worsening) occurred at an earlier age in USH1 patients carrying mutations in MYO7A.
Assuntos
DNA/genética , Proteínas da Matriz Extracelular/genética , Mutação , Miosinas/genética , Síndromes de Usher/genética , Acuidade Visual , Campos Visuais , Adolescente , Adulto , Análise Mutacional de DNA , Progressão da Doença , Eletrorretinografia , Proteínas da Matriz Extracelular/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Miosina VIIa , Miosinas/metabolismo , Fenótipo , Retina/diagnóstico por imagem , Retina/fisiopatologia , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Síndromes de Usher/diagnóstico , Síndromes de Usher/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: To evaluate the functional recovery of patients with symptomatic vitreomacular traction (VMT) after Ocriplasmin treatment. METHODS: Prospective, single centre, consecutive case series. Patients were treated with a single intravitreal injection of Ocriplasmin (Jetrea, Thrombogenics Inc, USA, Alcon/Novartis EU). The following outcome measures are considered: resolution of VMT, evaluated through the use of optical coherence tomography (SD-OCT), functional recovery evidenced by multifocal-electroretinogram (mfERG) and microperimetry (MP1) after treatment with Ocriplasmin. RESULTS: Four eyes of four patients were treated with Ocriplasmin injection. We observed a VMT non-surgical resolution in all patients. The longitudinal statistical analysis showed a significant improvement of best corrected visual acuity (BCVA) in the treated eye of about 0.97 letters/week (p = 0.033). No significant difference was observed in mean sensitivity (p > 0.05) assessed by MP1 in both eyes, while improvement in fixation stability was assessed in treated eyes (ß = 0.39; p = 0.029). In the four treated eyes mfERG revealed an increased foveal peak response over the follow-up. The longitudinal analysis of mfERG data shows a significant increase of N1 and P1 amplitude in the first rings and a significant decrease of N1 and P1 implicit time in most rings. CONCLUSIONS: We report on four cases with resolution of VMT after Ocriplasmin treatment. Our preliminary results demonstrate that Ocriplasmin is safe and effective in the treatment of VMT, because it not only leads to a morphological recovery but mostly to a restoration of macular functionality, evaluated through the use of different objective tests, such as MP1 and mfERG over a six-month follow-up.
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Fibrinolisina/uso terapêutico , Fibrinolíticos/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Doenças Retinianas/tratamento farmacológico , Idoso , Eletrorretinografia/métodos , Feminino , Fixação Ocular/fisiologia , Humanos , Injeções Intravítreas , Pessoa de Meia-Idade , Estudos Prospectivos , Doenças Retinianas/fisiopatologia , Perfurações Retinianas/tratamento farmacológico , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Descolamento do Vítreo/tratamento farmacológicoRESUMO
Gene therapy clinical trials with gene augmentation therapy for Leber Congenital Amaurosis have shown partial reversal of retinal dysfunction. Most studies described the effect of treatment in a single eye and limited evidence is reported in literature about patients treated in both eyes. In this chapter, we present the findings of a young patient treated in both eyes. Efficacy of the treatment was assessed with Best Corrected Visual Acuity, Goldman Visual Field testing, Esterman computerized binocular visual field and Microperimetric testing. Post-treatment results showed improvement of visual function in both eyes, in particular, a strong amelioration was observed after the first injection, by using conventional monocular tests. Moreover, the treatment in the second eye resulted in a further improvement of binocular visual functionality, as easily detected by computerized binocular visual field. In conclusion, our data suggest that gene therapy can inhibit retinal degeneration and can be safe and effective in restoring visual functionality in young subjects treated in both eyes. Finally, new outcome measurements, in particular binocular computerized visual field parameters, can therefore be useful to quantify overall visual gain in patients undergoing gene therapy in both eyes.
Assuntos
Olho/metabolismo , Terapia Genética/métodos , Amaurose Congênita de Leber/terapia , cis-trans-Isomerases/metabolismo , Criança , Dependovirus/genética , Seguimentos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Injeções , Itália , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/fisiopatologia , Resultado do Tratamento , Visão Binocular/fisiologia , Visão Ocular/fisiologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , cis-trans-Isomerases/genéticaRESUMO
BACKGROUND: Previous studies described cases of Ocriplasmin injections in patients with vitreo-macular traction and reduced central visual acuity. We describe the first case of a patient with 20/20 visual acuity and vitreo-macular traction treated with Ocriplasmin, and, for the first time in literature, we evaluated the functional changes of the macula in response to pharmacological treatment through multifocal-electroretinogram. CASE PRESENTATION: We report the case of a female Caucasian patient aged 67 years with vitreo-macular traction in the right eye, treated with Ocriplasmin, at the Eye Clinic of the Second University of Naples. Visual acuity was 20/20 before treatment, associated with metamorphopsia. Two weeks after injection, optical coherence tomography showed the release of vitreo-macular traction and multifocal electroretinogram responses showed a significant increase of retinal density responses in all six rings (p < 0.03). Visual acuity remained constant with resolution of symptoms and the appearance of vitreous floaters. CONCLUSION: Intravitreal injection of Ocriplasmin resulted to be a safe and effective treatment in the case here reported. Our data show that the anatomical recovery with release of vitreo-macular traction was associated with a full functional recovery. In fact, the electrical retinal density response of the macular area improved two weeks after Ocriplasmin injection. Further studies with broader inclusion criteria for Ocriplasmin treatment (e.g. also with visual acuity higher than 20/25) on a larger study sample are needed to confirm our results.
Assuntos
Fibrinolisina/uso terapêutico , Fibrinolíticos/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Doenças Retinianas/tratamento farmacológico , Acuidade Visual/fisiologia , Corpo Vítreo/efeitos dos fármacos , Idoso , Eletrorretinografia , Feminino , Humanos , Injeções Intravítreas , Retina/fisiologia , Doenças Retinianas/fisiopatologia , Aderências Teciduais/tratamento farmacológico , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: Single-access laparoscopic surgery is not used routinely for the treatment of colorectal disease. The aim of this retrospective cohort study is to compare the results of single-access laparoscopic rectal resection (SALR) versus multiaccess laparoscopic rectal resection with a mean follow-up of 24 months. METHODS: This retrospective cohort study enrolled 42 patients. Between January 2010 and June 2012, 21 SALRs were performed. These patients were compared with a group of 21 other patients who had undergone multiport laparoscopic rectal resection. This control group had the same exclusion criteria and patient demographics. Short-term outcomes were reassessed with a mean follow-up of 2 years. Statistical analysis included the Student t test and Fisher's exact test. Finally, we performed a differential cost analysis between the 2 procedures. RESULTS: Exclusion criteria, patient demographics, and indication for surgery were similar in both groups. The conversion rate was 0% in both groups. There were no intraoperative complications or deaths. Bowel recovery was similar in both groups. No interventions, readmissions, or deaths were recorded at 30 days' follow-up. At a mean follow-up of 24 months, all the patients with a preoperative diagnosis of cancer are still alive and disease free. Considering the selected 3 items, the mean cost per patient for single-access laparoscopic surgery and multiple-access laparoscopic surgery were estimated as 7213 and 7495 Euros, respectively. CONCLUSION: We think that SALR could be performed in selected patients by surgeons with high multiport laparoscopic skills. It is compulsory by law to evaluate outcomes and cost-effectiveness by using randomized controlled trials.
Assuntos
Laparoscopia , Doenças Retais/cirurgia , Reto/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Custos e Análise de Custo , Feminino , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Laparoscopia/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Orthostatic Hypotension is defined as a reduction of systolic and diastolic blood pressure within 3 minutes of standing, and may cause dizziness and loss of balance. Orthostatic Hypotension has been considered an important risk factor for falls since 1960. This paper presents a model to predict the systolic blood pressure drop due to orthostatic hypotension, relying on heart rate variability measurements extracted from 5 minute ECGs recorded before standing. This model was developed and validated with the leave-one-out cross-validation technique involving 10 healthy subjects, and finally tested with an additional 5 healthy subjects, whose data were not used during the training and cross-validation process. The results show that the model predicts correctly the systolic blood pressure drop in 80 % of all experiments, with an error rate below the measurement error of a sphygmomanometer digital device.
Assuntos
Pressão Sanguínea/fisiologia , Eletrocardiografia/métodos , Frequência Cardíaca/fisiologia , Hipotensão Ortostática/fisiopatologia , Acidentes por Quedas/prevenção & controle , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Reprodutibilidade dos TestesRESUMO
PURPOSE: To evaluate disease progression in a cohort of patients with a clinical and genetic diagnosis of Stargardt disease. DESIGN: Longitudinal cohort study. PARTICIPANTS: A total of 56 selected patients with a clinical and molecular diagnosis of Stargardt disease, an early age of onset, and a median follow-up length of 2 years. METHODS: Patients underwent routine examination, including full-field electroretinography, microperimetry, and optical coherence tomography. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), mean retinal sensitivity, fixation stability, preferred retinal locus, inner segment/outer segment (IS/OS) junction loss, and atrophic lesion area. RESULTS: A total of 56 patients with a mean age at disease onset of 15.3 years (range, 3-28 years), a mean disease duration of 12.1 years, and a mean age at baseline of 27.4 years were analyzed. The median BCVA was 20/200 in both eyes. Optical coherence tomography parameters (IS/OS alteration and retinal pigment epithelium lesion area) were obtained in only 49 patients because the signal quality was poor in the remaining 7 patients. Optical coherence tomography revealed a mean retinal pigment epithelium lesion area of 2.6 mm(2), preserved foveal IS/OS in 4.1% of patients, loss of foveal IS/OS in 59.2% of patients, and extensive loss of macular IS/OS in 36.7% of patients. Microperimetric findings showed a reduced macular sensitivity (mean, 10 decibels [dB]) and an unstable fixation in half of the patient cohort. The longitudinal analysis showed a significant progressive reduction of BCVA and macular sensitivity (at an estimated rate of 0.04 decimals and 1.19 dB/year, respectively) associated with a significant enlargement of retinal pigment epithelium lesion area (0.282 mm(2)/year). No significant changes in ophthalmoscopic findings and electroretinographic responses were detected. CONCLUSIONS: This study highlights the importance of microperimetry and optical coherence tomography in monitoring patients with Stargardt disease. Quantifying the decline of visual functionality and detecting morphologic macular changes prove useful in evaluating disease progression over a short-term follow-up and should be taken into account for the design of future clinical trials of gene therapy to treat retinal dystrophy.
Assuntos
Macula Lutea , Adolescente , Adulto , Idade de Início , Criança , Progressão da Doença , Eletrorretinografia , Feminino , Seguimentos , Fundo de Olho , Humanos , Estudos Longitudinais , Macula Lutea/patologia , Macula Lutea/fisiologia , Degeneração Macular/patologia , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Doença de Stargardt , Tomografia de Coerência Óptica , Acuidade Visual , Campos Visuais/fisiologia , Adulto JovemRESUMO
BACKGROUND: To compare accuracy in intraocular lens (IOL) power calculation in eyes undergoing combined cataract and Descemet stripping and automated endothelial keratoplasty (C-DSAEK) surgery of the following formulas: Barrett Universal II, EVO, Haigis, Hoffer Q, Holladay 2, Kane and SRK/T. METHODS: 72 eyes from 72 patients (38 males, (53%)) with a mean age 68.08 ± 8.69 years (from 44 to 88 years old) underwent combined C-DSAEK were included. The IOL powers to implant were calculated with Barrett Universal II formula targeting -1 D refraction. Preoperative and postoperative data were used to obtain the median of absolute prediction errors (MAE) targeting emmetropia with every tested formula. RESULTS: Means of MAE calculated were +1.45 D for Barrett Universal II, +1.37 D for EVO, +1.48 D for Haigis, +1.38 D for Hoffer Q, +1.37 D for Holladay 2, +1.39 D for Kane and +1.31 D for SRK/T. SRK/T MAE showed major significant (p < 0.01) differences compared to the other formulas. DISCUSSION: Even if tested formulas are not able to accurately target emmetropia, SRK/T seems to be able to provide closer results in eyes undergoing C-DSAEK.
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Biallelic mutations in the RPE65 gene affect nearly 8% of Leber Congenital Amaurosis and 2% of Retinitis Pigmentosa cases. Voretigene neparvovec (VN) is the first gene therapy approach approved for their treatment. To date, real life experience has demonstrated functional improvements following VN treatment, which are consistent with the clinical trials outcomes. However, there is currently no consensus on the characteristics for eligibility for VN treatment. We reviewed relevant literature to explore whether recommendations on patient eligibility can be extrapolated following VN marketing. We screened 166 papers through six research questions, following scoping reviews methodology, to investigate: (1) the clinical and genetic features considered in VN treatment eligibility; (2) the psychophysical tests and imaging modalities used in the pre-treatment and follow-up; (3) the potential correlations between visual function and retinal structure that can be used to define treatment impact on disease progression; (4) retinal degeneration; (5) the most advanced testing modalities; and (6) the impact of surgical procedure on treatment outcomes. Current gaps concerning patients' eligibility in clinical settings, such as pre-treatment characteristics and outcomes are not consistently reported across the studies. No upper limit of retinal degeneration can be defined as the univocal factor in patient eligibility, although evidence suggested that the potential for function rescue is related to the preservation of photoreceptors before treatment. In general, paediatric patients retain more viable cells, present a less severe disease stage and show the highest potential for improvements, making them the most suitable candidates for treatment.
RESUMO
PURPOSE: To assess the efficacy of voretigene neparvovec (VN) treatment by objective fixation stability and chromatic pupillometry testing in clinical practice. DESIGN: Retrospective cohort study with longitudinal follow-up. SUBJECTS: Twelve patients (aged 7-34 years) with RPE65-related inherited retinal dystrophies were treated at the same center with VN in both eyes. METHODS: Patients treated at the same center with VN were evaluated over a 12-month posttreatment follow-up by subjective and objective tests. Furthermore, patients treated with VN who developed atrophy were compared with those who did not. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), full-field stimulus threshold test (FST), semiautomated kinetic visual field (SKVF), microperimetry, and chromatic pupillometry over a 12-month follow-up. RESULTS: Significant improvements of BCVA (P < 0.001), SKVF (P < 0.05), and FST (P < 0.001) were already observed 45 days after treatment and were maintained at the 12-month timepoint. Fixation stability, assessed by microperimetry, improved significantly (P < 0.05) after treatment. Chromatic pupillometry showed significant improvements (P < 0.05) at the 6- and 12-month timepoints. The increase in maximum pupillary constriction significantly (P < 0.001) correlated with higher retinal sensitivity in FST. Four patients developed multifocal retinal atrophy in both eyes, detected at the 6-month timepoint, but this atrophy was not generally associated with worse visual function outcomes. CONCLUSIONS: This study explores objective outcomes in order to demonstrate the efficacy of VN treatment in addition to the tests normally performed in clinical practice. Our findings show a significant improvement of retinal function both in subjective assessments, such as BCVA, SKVF, and FST, and in objective measurements of fixation stability and maximum pupillary constriction. Moreover, the significant correlation between maximum pupillary constriction and light sensitivity thresholds corroborates the introduction of chromatic pupillometry as an objective test to better assess treatment outcomes in patients with inherited retinal dystrophies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references in the Footnotes and Disclosures at the end of this article.
Assuntos
Distrofias Retinianas , Acuidade Visual , Campos Visuais , cis-trans-Isomerases , Humanos , Masculino , Feminino , Adolescente , Estudos Retrospectivos , Criança , Adulto , Acuidade Visual/fisiologia , Adulto Jovem , Seguimentos , Campos Visuais/fisiologia , cis-trans-Isomerases/genética , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/fisiopatologia , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , Resultado do Tratamento , Terapia Genética/métodos , Testes de Campo VisualRESUMO
BACKGROUND: Telemedicine, a term that encompasses several applications and tasks, generally involves the remote management and treatment of patients by physicians. It is known as transversal telemedicine when practiced among health care professionals (HCPs). OBJECTIVE: We describe the experience of implementing our telemedicine Eumeda platform for HCPs over the last 10 years. METHODS: A web-based informatics platform was developed that had continuously updated hypertext created using advanced technology and the following features: security, data insertion, dedicated software for image analysis, and the ability to export data for statistical surveys. Customizable files called "modules" were designed and built for different fields of medicine, mainly in the ophthalmology subspecialty. Each module was used by HCPs with different authorization profiles. IMPLEMENTATION (RESULTS): Twelve representative modules for different projects are presented in this manuscript. These modules evolved over time, with varying degrees of interconnectivity, including the participation of a number of centers in 19 cities across Italy. The number of HCP operators involved in each single module ranged from 6 to 114 (average 21.8, SD 28.5). Data related to 2574 participants were inserted across all the modules. The average percentage of completed text/image fields in the 12 modules was 65.7%. All modules were evaluated in terms of access, acceptability, and medical efficacy. In their final evaluation, the participants judged the modules to be useful and efficient for clinical use. CONCLUSIONS: Our results demonstrate the usefulness of the telemedicine platform for HCPs in terms of improved knowledge in medicine, patient care, scientific research, teaching, and the choice of therapies. It would be useful to start similar projects across various health care fields, considering that in the near future medicine as we know it will completely change.
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Purpose: We investigated the natural history of retinal dystrophy owing to variants in the MYO7A gene. Methods: Fifty-three patients (mean age, 33.6 ± 16.7 years) with Usher syndrome owing to biallelic, mostly pathogenic, variants in MYO7A underwent baseline and two annual follow-up visits. Best-corrected visual acuity (BCVA), semiautomatic kinetic visual field, full-field electroretinogram, color fundus imaging, microperimetry, spectral-domain optical coherence tomography, and fundus autofluorescence were assessed. Results: At baseline, all patients presented with decreased BCVA (66.4 ± 17.9 Early Treatment Diabetic Retinopathy score and 59.5 ± 21.7 Early Treatment Diabetic Retinopathy score, in the better- and worse-seeing eyes, respectively), restricted semiautomatic kinetic visual field (III4e area, 3365.8 ± 4142.1°2; 4176.4 ± 4400.3°2) and decreased macular sensitivity (9.7 ± 9.9 dB; 9.0 ± 10.2 dB). Spectral-domain optical coherence tomography revealed reduced central macular thickness (259.6 ± 63.0 µm; 250.7 ± 63.3 µm) and narrowed ellipsoid zone band width (2807.5 ± 2374.6 µm; 2615.5 ± 2370.4 µm). Longitudinal analyses (50 patients) showed a significant decrease of BCVA in better-seeing eyes, whereas no changes were observed in worse-seeing eyes for any parameter. BCVA, semiautomatic kinetic visual field (III4e and V4e) and macular sensitivity were related significantly to age at baseline. Hyperautofluorescent foveal patch (16 eyes [31.4%]) and abnormal central hypoautofluorescence (9 eyes [17.6%]) were significantly associated with worse morphological and functional read-outs compared with the hyperautofluorescent ring pattern (22 eyes [43.1%]). Conclusions: Our European multicentric study offers the first prospective longitudinal analysis in one of the largest cohorts of MYO7A patients described to date, confirming the slow disease progression. More important, this study emphasizes the key role of fundus autofluorescence patterns in retinal impairment staging and advocates its adoption as an objective biomarker in patient selection for future gene therapy clinical trials.
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Eletrorretinografia , Terapia Genética , Miosina VIIa , Tomografia de Coerência Óptica , Síndromes de Usher , Acuidade Visual , Campos Visuais , Humanos , Masculino , Feminino , Adulto , Estudos Prospectivos , Tomografia de Coerência Óptica/métodos , Acuidade Visual/fisiologia , Pessoa de Meia-Idade , Campos Visuais/fisiologia , Adulto Jovem , Adolescente , Síndromes de Usher/genética , Síndromes de Usher/fisiopatologia , Síndromes de Usher/terapia , Síndromes de Usher/diagnóstico , Terapia Genética/métodos , Criança , Testes de Campo Visual , Europa (Continente) , Angiofluoresceinografia , Seguimentos , Idoso , Estudos Longitudinais , Progressão da Doença , Miosinas/genética , Retina/diagnóstico por imagem , Retina/fisiopatologia , Retina/patologiaRESUMO
OBJECTIVE: The aim of this study was to show the clinical data of long-term (3-year) follow-up of 5 patients affected by Leber congenital amaurosis type 2 (LCA2) treated with a single unilateral injection of adeno-associated virus AAV2-hRPE65v2. DESIGN: Clinical trial. PARTICIPANTS: Five LCA2 patients with RPE65 gene mutations. METHODS: After informed consent and confirmation of trial eligibility criteria, the eye with worse visual function was selected for subretinal delivery of adeno-associated virus (AAV2-hRPE65v2). Subjects were evaluated before and after surgery at designated follow-up visits (1, 2, 3, 14, 30, 60, 90, 180, 270, and 365 days, 1.5 years, and 3 years) by complete ophthalmic examination. Efficacy for each subject was monitored with best-corrected visual acuity, kinetic visual field, nystagmus testing, and pupillary light reflex. MAIN OUTCOME MEASURES: Best-corrected visual acuity, kinetic visual field, nystagmus testing, and pupillary light reflex. RESULTS: The data showed a statistically significant improvement of best-corrected visual acuity between baseline and 3 years after treatment in the treated eye (P<0.001). In all patients, an enlargement of the area of visual field was observed that remained stable until 3 years after injection (average values: baseline, 1058 deg(2) vs. 3 years after treatment, 4630 deg(2)) and a reduction of the nystagmus frequency compared with baseline at the 3-year time point. Furthermore, a statistically significant difference was observed in the pupillary constriction of the treated eye (P<0.05) compared with the untreated eye in 3 patients at 1- and 3-year time points. No patients experienced serious adverse events related to the vector in the 3-year postinjection period. CONCLUSIONS: The long-term follow-up data (3 years) on the 5-patient Italian cohort involved in the LCA2 gene therapy clinical trial clearly showed a stability of improvement in visual and retinal function that had been achieved a few months after treatment. Longitudinal data analysis showed that the maximum improvement was achieved within 6 months after treatment, and the visual improvement was stable up to the last observed time point. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
Assuntos
Dependovirus/genética , Terapia Genética , Amaurose Congênita de Leber/terapia , cis-trans-Isomerases/genética , Adolescente , Adulto , Criança , Feminino , Seguimentos , Vetores Genéticos , Humanos , Injeções Intraoculares , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/fisiopatologia , Masculino , Mutação , Reflexo Pupilar/fisiologia , Tomografia de Coerência Óptica , Transfecção , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Adulto JovemRESUMO
OBJECTIVES: To compare choroidal vascularity index (CVI) measurements using the automated image binarization algorithm in healthy subjects with two Spectralis spectral-domain optical coherence tomography (SD-OCT) protocol scans. METHODS: Sixty-nine eyes of 69 healthy volunteers were included in this cross-sectional prospective study. Two subsequent horizontal 20°line scans passing through the fovea were acquired with enhanced-depth imaging mode with high speed (HS) and high resolution (HR) protocol scans. CVI and its subcomponents were measured with the previously validated automated algorithm. Differences between choroidal measurements obtained with HS and HR protocol scans were evaluated with t-test and Bland & Altman plots. RESULTS: A total of 33 male (47.8%) and 36 female (52.2%) subjects with a mean age of 35.1 ± 13.4 years were included. Overall, HS protocol scan was associated with significant lower values of total choroidal area (-0.047 mm2) and stromal choroidal area (-0.036 mm2), and a significant greater value of CVI (+0.010%) if compared to HR protocol. Luminal choroidal area was lower when calculated with the HS protocol, although it did not reach significance. To compare the two different protocols, the number of pixels should be multiplied for 3.87 ×5.73 when the CVI is measured on a HR OCT b scan and 3.87 ×11.46 for the HS OCT b scan. CONCLUSIONS: HS and HR acquisition modes significantly influence CVI and its subcomponents values measured with the automated software. However, adopting the scale factors can minimize the differences between the two protocol scans.
Assuntos
Corioide , Tomografia de Coerência Óptica , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Tomografia de Coerência Óptica/métodos , Estudos Transversais , Estudos Prospectivos , AlgoritmosRESUMO
BACKGROUND: To perform a multimodal assessment of the ectopic inner foveal layers' (EIFL) prognostic role on idiopathic epiretinal membrane (ERM) surgery. METHODS: We retrospectively followed-up for 12 months 27 patients who underwent ERM surgery and stratified them based on EIFL presence (group 1) or absence (group 2) at baseline. Central Retinal Thickness (CRT) and best-corrected visual acuity (BCVA) were compared pre- and post-operatively at 1, 4 and 12 months, whereas fixation stability (FS), macular sensitivity (MS) and multifocal electroretinogram (mfERG) responses were confronted at baseline and 12 months. RESULTS: In group 1, BCVA improved at 4 and 12 months (MD = 0.14 (SE = 0.04); MD = 0.13 (SE = 0.05), respectively) as well as in group 2 (MD = 0.31 (SE = 0.07); MD = 0.41 (SE = 0.08), respectively). CRT did not change in group 1, whereas it decreased in group 2 at 4 and 12 months (MD = -73.13; SE = 23.56; MD = -76.20; SE = 23.56). MS showed no changes in both groups after surgery. FS did not change in group 1, whereas group 2 improved FS 2° (+8.91 ± 13.97) and FS 4° (+4.33 ± 3.84). MfERG P1 wave did not change in group 1, while in group 2 αP1-2, αP1-3 and αP1-4 improved postoperatively (27.97 ± 27.62; 12.51 ± 17.36; 10.49 ± 17.19, respectively). CONCLUSIONS: Multimodal assessment confirmed that EIFL negatively affected ERM surgery outcomes.
RESUMO
BACKGROUND: To evaluate corneal deformation in Maturity Onset Diabetes of the Young type 2 (MODY2), paediatric subjects were analysed using a Scheimpflug-based device. The purpose of this analysis was to find new biomarkers for MODY2 disease and to gain a better understanding of the pathogenesis of the disease. METHODS: A total of 15 patients with genetic and metabolic diagnoses of MODY2 (mean age 12.8 ± 5.66 years) and 15 age-matched healthy subjects were included. The biochemical and anthropometric data of MODY2 patients were collected from clinical records, and a complete ophthalmic check with a Pentacam HR EM-3000 Specular Microscope and Corvis ST devices was performed in both groups. RESULTS: Highest concavity (HC) deflection length, Applanation 1 (A1) deflection amplitude, and A1 deflection area showed significantly lower values in MODY2 patients compared to healthy subjects. A significant positive correlation was observed between Body Mass Index (BMI) and HC deflection area and between waist circumference (WC) and the following parameters: maximum deformation amplitude, HC deformation amplitude, and HC deflection area. The glycosylated hemoglobin level (HbA1c) showed a significant positive correlation with Applanation 2 time and HC time. CONCLUSIONS: The obtained results show, for the first time, differences regarding corneal distortion features in the MODY2 population compared with healthy eyes.
RESUMO
Gene therapy of Usher syndrome type 1B (USH1B) due to mutations in the large Myosin VIIA (MYO7A) gene is limited by the packaging capacity of adeno-associated viral (AAV) vectors. To overcome this, we have previously developed dual AAV8 vectors which encode human MYO7A (dual AAV8.MYO7A). Here we show that subretinal administration of 1.37E+9 to 1.37E+10 genome copies of a good-manufacturing-practice-like lot of dual AAV8.MYO7A improves the retinal defects of a mouse model of USH1B. The same lot was used in non-human primates at doses 1.6× and 4.3× the highest dose proposed for the clinical trial which was based on mouse efficacy data. Long-lasting alterations in retinal function and morphology were observed following subretinal administration of dual AAV8.MYO7A at the high dose. These findings were modest and improved over time in the low-dose group, as also observed in other studies involving the use of AAV8 in non-human primates and humans. Biodistribution and shedding studies confirmed the presence of vector DNA mainly in the visual pathway. Accordingly, we detected human MYO7A mRNA expression predominantly in the retina. Overall, these studies pave the way for the clinical translation of subretinal administration of dual AAV vectors in USH1B subjects.